ANORO delivers superior lung function vs ADVAIR DISKUS for COPD1

ANORO ELLIPTA is a combination anticholinergic/LABA for the maintenance treatment of airflow obstruction in patients with COPD.

ADVAIR DISKUS 250/50 mcg, an ICS/LABA, is for the maintenance treatment of airflow obstruction in patients with COPD and for reducing exacerbations in patients with a history of exacerbations.

Studied in patients with moderate to severe COPD (GOLD 2 or 3).

Description of Studies1,2

The efficacy and safety of a once-daily dose of ANORO ELLIPTA and a twice-daily dose of ADVAIR DISKUS 250 mcg/50 mcg were evaluated in 12-week, multicenter, randomized, double-blind, double-dummy, parallel-group studies in patients (mean age range: 63 to 64 years) with COPD with no exacerbations (COPD symptoms requiring oral corticosteroids, antibiotics, and/or hospitalization) in the previous year. At screening, patients had a mean postbronchodilator FEV1 range of 49.4% to 49.5% predicted.

Primary endpoint

Proportion of patients achieving an increase in trough FEV1 ≥100 mL above baseline at Day 85

Other endpoint: Endpoint was not adjusted for multiplicity

ANORO ELLIPTA

ADVAIR DISKUS 250/50 mcg

VS ADVAIR DISKUS 250/50

Patients taking ANORO had 2x greater odds of experiencing a ≥100 mL improvement from baseline in trough FEV1 at Day 85

ANORO ELLIPTA

ADVAIR DISKUS 250/50 mcg

Studied in patients with moderate to severe COPD (GOLD 2 or 3).

Description of Studies

See description of studies above.

Other efficacy endpoint

Proportion of patients achieving an increase of ≥100 mL above baseline in trough FEV1 at Day 85.

ANORO: Rescue medication use vs ADVAIR DISKUS for COPD1

Rescue albuterol puffs per day over 12 weeks

Other endpoint: Endpoint was not adjusted for multiplicity

Studied in patients with moderate to severe COPD (GOLD 2 or 3).

Description of Studies1,2

See description of studies above. These studies were not designed to demonstrate noninferiority between treatment groups.

Other efficacy endpoint

Rescue albuterol use (puffs/day), Weeks 1 to 12.

See Rescue Albuterol Use vs Placebo below.

Adverse events occurring in ≥3% of subjects in the 2 studies1

Safety data are descriptive only. The studies were not powered to compare the safety profiles of the products.

ANORO is from GSK, the maker of

Rescue Albuterol Use vs Placebo2-4

Study DB21133732,3

A 24-week, double-blind, placebo-controlled study evaluated the efficacy and safety of ANORO ELLIPTA (n=413), placebo (n=280), and other treatment arms in patients with COPD. The primary endpoint was trough FEV1 at Day 169. For the other endpoint of rescue albuterol use (puffs/day), Weeks 1 to 24, the LS mean number of rescue albuterol puffs per day was 3.3 for ANORO and 4.1 for placebo, which corresponds to a 0.8 difference. This endpoint was not adjusted for multiplicity.

Study 2012112,4

A 12-week, double-blind, placebo-controlled study evaluated the efficacy and safety of ANORO ELLIPTA (n=248) compared with placebo (n=248) in patients with COPD. The primary endpoint was the SGRQ total score at Week 12. For the secondary endpoint of rescue albuterol use (puffs/day), Weeks 1 to 12, the LS mean number of rescue albuterol puffs per day was 2.2 for ANORO and 2.9 for placebo, which corresponds to a 0.7 difference (P<0.001).

Important Safety Information for ANORO ELLIPTA

WARNING: ASTHMA-RELATED DEATH

Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, one of the active ingredients in ANORO, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths. This finding with salmeterol is considered a class effect of all LABA.

The safety and efficacy of ANORO in patients with asthma have not been established. ANORO is not indicated for the treatment of asthma.

CONTRAINDICATIONS

ANORO is contraindicated in patients with severe hypersensitivity to milk proteins or with hypersensitivity to umeclidinium, vilanterol, or any of the excipients.

WARNINGS AND PRECAUTIONS

ANORO should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD.

ANORO is NOT a rescue medication and should NOT be used for the relief of acute bronchospasm or symptoms. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

ANORO should not be used more often or at higher doses than recommended or with another LABA (eg, salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs, like LABA.

Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of ANORO. Discontinue ANORO if such reactions occur.

Vilanterol can produce clinically significant cardiovascular effects in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, or symptoms. If such effects occur, ANORO may need to be discontinued. ANORO should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

Use with caution in patients with narrow-angle glaucoma. Instruct patients to contact a healthcare provider immediately if signs or symptoms of acute narrow-angle glaucoma develop.

Use with caution in patients with urinary retention, especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to contact a healthcare provider immediately if signs or symptoms of urinary retention develop.

DRUG INTERACTIONS

Caution should be exercised when considering the coadministration of ANORO with ketoconazole and other known strong CYP3A4 inhibitors as increased systemic exposure to vilanterol and cardiovascular adverse effects may occur. See prior Warning and Precaution regarding CYP3A4 inhibitors.

ANORO should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval, or within 2 weeks of discontinuation of such agents, because they may potentiate the effect of vilanterol on the cardiovascular system.

Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as vilanterol, but may produce severe bronchospasm in patients with COPD.

Use with caution in patients taking non–potassium-sparing diuretics, as ECG changes and/or hypokalemia associated with these diuretics may worsen with concomitant beta-agonists.

Avoid coadministration of ANORO with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.

Important Safety Information for ADVAIR DISKUS 250/50 for COPD

CONTRAINDICATIONS

ADVAIR DISKUS is contraindicated for primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.

ADVAIR DISKUS is contraindicated in patients with severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients.

Important Safety Information for ADVAIR DISKUS 250/50 for COPD

CONTRAINDICATIONS

ADVAIR DISKUS is contraindicated for primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.

ADVAIR DISKUS is contraindicated in patients with severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients.

WARNINGS AND PRECAUTIONS

LABA monotherapy for asthma increases the risk of asthma-related death, and in pediatric and adolescent patients, available data also suggest an increased risk of asthma-related hospitalization. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.

ADVAIR DISKUS should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD.

ADVAIR DISKUS should not be used for the relief of acute symptoms, ie, as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not ADVAIR DISKUS, should be used to relieve acute symptoms such as shortness of breath.

ADVAIR DISKUS should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using ADVAIR DISKUS should not use another medicine containing a LABA (eg, salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol, vilanterol) for any reason.

Oropharyngeal candidiasis has occurred in patients treated with ADVAIR DISKUS. Advise patients to rinse the mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

There is an increased risk of pneumonia with ADVAIR DISKUS in patients with COPD.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical features of pneumonia and exacerbations frequently overlap.

– In 2 replicate 1-year trials in 1579 subjects with COPD with a history of exacerbations, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in subjects treated with ADVAIR DISKUS 250/50 was higher in subjects over 65 years of age (9%) compared to the incidence in subjects under 65 years of age (4%).

– In a 3-year trial in 6184 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 500/50 compared with placebo (16% receiving ADVAIR DISKUS 500/50, 14% receiving fluticasone propionate 500 mcg, 11% receiving salmeterol 50 mcg, and 9% receiving placebo). The incidence of pneumonia was higher in subjects over 65 years of age (18% with ADVAIR DISKUS 500/50 vs 10% with placebo) compared with subjects less than 65 years of age (14% with ADVAIR DISKUS 500/50 vs 8% with placebo).

Patients who use corticosteroids are at risk for potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. A more serious or even fatal course of chickenpox or measles may occur in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections.

Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. Slowly taper the dose of systemic corticosteroids if transferring patients to ADVAIR DISKUS.

Hypercorticism and adrenal suppression may occur with high doses of inhaled corticosteroids, including fluticasone propionate, or at the recommended dose in susceptible individuals. If such effects occur, discontinue ADVAIR DISKUS slowly.

Salmeterol, a component of ADVAIR DISKUS, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. If such effects occur, ADVAIR DISKUS may need to be discontinued. ADVAIR DISKUS should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (eg, anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating ADVAIR DISKUS 250/50 and periodically thereafter.

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long‐term administration of inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR DISKUS. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

Be alert to hypokalemia, hyperglycemia, and systemic eosinophilic conditions, such as Churg-Strauss syndrome.

Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

In the two 1-year trials, the most common events that occurred with a frequency of >5% and more frequently in the subjects treated with ADVAIR DISKUS 250/50 than with salmeterol were nasopharyngitis, upper respiratory tract infection, nasal congestion, back pain, sinusitis, dizziness, nausea, pneumonia, candidiasis, and dysphonia.

ADVAIR DISKUS should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of ADVAIR DISKUS, on the vascular system may be potentiated by these agents.

Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of ADVAIR DISKUS, but may also produce severe bronchospasm in patients with asthma or COPD.

Use ADVAIR DISKUS with caution in patients taking non–potassium-sparing diuretics (such as loop or thiazide diuretics), as electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with coadministration with beta-agonists, such as salmeterol.

USE IN SPECIFIC POPULATIONS

Fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism. Impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.

The effects of corticosteroids in the treatment of COPD are not well defined, and inhaled corticosteroids, when used apart from approved combination products, are not indicated for COPD.

Important Safety Information for ANORO ELLIPTA

WARNING: ASTHMA-RELATED DEATH

Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, one of the active ingredients in ANORO, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths. This finding with salmeterol is considered a class effect of all LABA.

The safety and efficacy of ANORO in patients with asthma have not been established. ANORO is not indicated for the treatment of asthma.

CONTRAINDICATIONS

ANORO is contraindicated in patients with severe hypersensitivity to milk proteins or with hypersensitivity to umeclidinium, vilanterol, or any of the excipients.

WARNINGS AND PRECAUTIONS

ANORO should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD.

ANORO is NOT a rescue medication and should NOT be used for the relief of acute bronchospasm or symptoms. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

ANORO should not be used more often or at higher doses than recommended or with another LABA (eg, salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs, like LABA.

Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of ANORO. Discontinue ANORO if such reactions occur.

Vilanterol can produce clinically significant cardiovascular effects in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, or symptoms. If such effects occur, ANORO may need to be discontinued. ANORO should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

Use with caution in patients with narrow-angle glaucoma. Instruct patients to contact a healthcare provider immediately if signs or symptoms of acute narrow-angle glaucoma develop.

Use with caution in patients with urinary retention, especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to contact a healthcare provider immediately if signs or symptoms of urinary retention develop.

DRUG INTERACTIONS

Caution should be exercised when considering the coadministration of ANORO with ketoconazole and other known strong CYP3A4 inhibitors as increased systemic exposure to vilanterol and cardiovascular adverse effects may occur. See prior Warning and Precaution regarding CYP3A4 inhibitors.

ANORO should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval, or within 2 weeks of discontinuation of such agents, because they may potentiate the effect of vilanterol on the cardiovascular system.

Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as vilanterol, but may produce severe bronchospasm in patients with COPD.

Use with caution in patients taking non–potassium-sparing diuretics, as ECG changes and/or hypokalemia associated with these diuretics may worsen with concomitant beta-agonists.

Avoid coadministration of ANORO with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.

Important Safety Information for ADVAIR DISKUS 250/50 for COPD

CONTRAINDICATIONS

ADVAIR DISKUS is contraindicated for primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.

ADVAIR DISKUS is contraindicated in patients with severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients.

Important Safety Information for ADVAIR DISKUS 250/50 for COPD

CONTRAINDICATIONS

ADVAIR DISKUS is contraindicated for primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.

ADVAIR DISKUS is contraindicated in patients with severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients.

WARNINGS AND PRECAUTIONS

LABA monotherapy for asthma increases the risk of asthma-related death, and in pediatric and adolescent patients, available data also suggest an increased risk of asthma-related hospitalization. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.

ADVAIR DISKUS should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD.

ADVAIR DISKUS should not be used for the relief of acute symptoms, ie, as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not ADVAIR DISKUS, should be used to relieve acute symptoms such as shortness of breath.

ADVAIR DISKUS should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using ADVAIR DISKUS should not use another medicine containing a LABA (eg, salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol, vilanterol) for any reason.

Oropharyngeal candidiasis has occurred in patients treated with ADVAIR DISKUS. Advise patients to rinse the mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

There is an increased risk of pneumonia with ADVAIR DISKUS in patients with COPD.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical features of pneumonia and exacerbations frequently overlap.

– In 2 replicate 1-year trials in 1579 subjects with COPD with a history of exacerbations, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in subjects treated with ADVAIR DISKUS 250/50 was higher in subjects over 65 years of age (9%) compared to the incidence in subjects under 65 years of age (4%).

– In a 3-year trial in 6184 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 500/50 compared with placebo (16% receiving ADVAIR DISKUS 500/50, 14% receiving fluticasone propionate 500 mcg, 11% receiving salmeterol 50 mcg, and 9% receiving placebo). The incidence of pneumonia was higher in subjects over 65 years of age (18% with ADVAIR DISKUS 500/50 vs 10% with placebo) compared with subjects less than 65 years of age (14% with ADVAIR DISKUS 500/50 vs 8% with placebo).

Patients who use corticosteroids are at risk for potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. A more serious or even fatal course of chickenpox or measles may occur in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections.

Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. Slowly taper the dose of systemic corticosteroids if transferring patients to ADVAIR DISKUS.

Hypercorticism and adrenal suppression may occur with high doses of inhaled corticosteroids, including fluticasone propionate, or at the recommended dose in susceptible individuals. If such effects occur, discontinue ADVAIR DISKUS slowly.

Salmeterol, a component of ADVAIR DISKUS, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. If such effects occur, ADVAIR DISKUS may need to be discontinued. ADVAIR DISKUS should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (eg, anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating ADVAIR DISKUS 250/50 and periodically thereafter.

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long‐term administration of inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR DISKUS. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

Be alert to hypokalemia, hyperglycemia, and systemic eosinophilic conditions, such as Churg-Strauss syndrome.

Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

In the two 1-year trials, the most common events that occurred with a frequency of >5% and more frequently in the subjects treated with ADVAIR DISKUS 250/50 than with salmeterol were nasopharyngitis, upper respiratory tract infection, nasal congestion, back pain, sinusitis, dizziness, nausea, pneumonia, candidiasis, and dysphonia.

ADVAIR DISKUS should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of ADVAIR DISKUS, on the vascular system may be potentiated by these agents.

Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of ADVAIR DISKUS, but may also produce severe bronchospasm in patients with asthma or COPD.

Use ADVAIR DISKUS with caution in patients taking non–potassium-sparing diuretics (such as loop or thiazide diuretics), as electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with coadministration with beta-agonists, such as salmeterol.

USE IN SPECIFIC POPULATIONS

Fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism. Impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.

The effects of corticosteroids in the treatment of COPD are not well defined, and inhaled corticosteroids, when used apart from approved combination products, are not indicated for COPD.

Important Safety Information for ADVAIR DISKUS 250/50 for COPD

WARNING: ASTHMA-RELATED DEATH

Long-acting beta2-adrenergic agonists (LABA), such as salmeterol, one of the active ingredients in ADVAIR DISKUS, increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of salmeterol with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol (13 deaths out of 13,176 subjects treated for 28 weeks on salmeterol versus 3 deaths out of 13,179 subjects on placebo). Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA.

CONTRAINDICATIONS

ADVAIR DISKUS is contraindicated for primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.

ADVAIR DISKUS is contraindicated in patients with severe hypersensitivity to milk proteins.

WARNINGS AND PRECAUTIONS

ADVAIR DISKUS should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD.

ADVAIR DISKUS should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not ADVAIR DISKUS, should be used to relieve acute symptoms such as shortness of breath.

ADVAIR DISKUS should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using ADVAIR DISKUS should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol, vilanterol) for any reason.

Oropharyngeal candidiasis has occurred in patients treated with ADVAIR DISKUS. Advise patients to rinse the mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

PNEUMONIA WARNING

There is an increased risk of pneumonia with ADVAIR DISKUS in patients with COPD.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical features of pneumonia and exacerbations frequently overlap.

In 2 replicate 1-year trials in 1579 subjects with COPD with a history of exacerbations, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in subjects treated with ADVAIR DISKUS 250/50 was higher in subjects over 65 years of age (9%) compared to the incidence in subjects under 65 years of age (4%).

In a 3-year trial in 6184 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 500/50 compared with placebo (16% receiving ADVAIR DISKUS 500/50, 14% receiving fluticasone propionate 500 mcg, 11% receiving salmeterol 50 mcg, and 9% receiving placebo). The incidence of pneumonia was higher in subjects over 65 years of age (18% with ADVAIR DISKUS 500/50 vs 10% with placebo) compared with subjects less than 65 years of age (14% with ADVAIR DISKUS 500/50 vs 8% with placebo).

WARNINGS AND PRECAUTIONS (cont'd)

Patients who use corticosteroids are at risk for potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. A more serious or even fatal course of chickenpox or measles may occur in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections.

Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. Slowly taper the dose of systemic corticosteroids if transferring patients to ADVAIR DISKUS.

Hypercorticism and adrenal suppression may occur with high doses of inhaled corticosteroids, including fluticasone propionate, or at the recommended dose in susceptible individuals. If such effects occur, discontinue ADVAIR DISKUS slowly.

Salmeterol, a component of ADVAIR DISKUS, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. If such effects occur, ADVAIR DISKUS may need to be discontinued. ADVAIR DISKUS should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating ADVAIR DISKUS 250/50 and periodically thereafter.

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long-term administration of inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR DISKUS. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

Be alert to hypokalemia, hyperglycemia, and systemic eosinophilic conditions, such as Churg-Strauss syndrome.

Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

In the two 1-year trials, the most common events that occurred with a frequency of >5% and more frequently in the subjects treated with ADVAIR DISKUS 250/50 than with salmeterol were nasopharyngitis, upper respiratory tract infection, nasal congestion, back pain, sinusitis, dizziness, nausea, pneumonia, candidiasis, and dysphonia.

ADVAIR DISKUS should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of ADVAIR DISKUS, on the vascular system may be potentiated by these agents.

Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of ADVAIR DISKUS, but may also produce severe bronchospasm in patients with asthma or COPD.

Use ADVAIR DISKUS with caution in patients taking non–potassium-sparing diuretics (such as loop or thiazide diuretics), as electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with coadministration with beta-agonists, such as salmeterol.

USE IN SPECIFIC POPULATIONS

Fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism. Impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma.
Therefore, patients with hepatic disease should be closely monitored.

The effects of corticosteroids in the treatment of COPD are not well defined, and inhaled corticosteroids, when used apart from approved combination products, are not indicated for COPD.

Important Safety Information for ANORO ELLIPTA

WARNING: ASTHMA-RELATED DEATH

Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, one of the active ingredients in ANORO, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths. This finding with salmeterol is considered a class effect of all LABA.

The safety and efficacy of ANORO in patients with asthma have not been established. ANORO is not indicated for the treatment of asthma.

CONTRAINDICATIONS

ANORO is contraindicated in patients with severe hypersensitivity to milk proteins or with hypersensitivity to umeclidinium, vilanterol, or any of the excipients.

WARNINGS AND PRECAUTIONS

ANORO should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD.

ANORO is NOT a rescue medication and should NOT be used for the relief of acute bronchospasm or symptoms. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

ANORO should not be used more often or at higher doses than recommended or with another LABA (eg, salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs, like LABA.

Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of ANORO. Discontinue ANORO if such reactions occur.

Vilanterol can produce clinically significant cardiovascular effects in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, or symptoms. If such effects occur, ANORO may need to be discontinued. ANORO should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

Use with caution in patients with narrow-angle glaucoma. Instruct patients to contact a healthcare provider immediately if signs or symptoms of acute narrow-angle glaucoma develop.

Use with caution in patients with urinary retention, especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to contact a healthcare provider immediately if signs or symptoms of urinary retention develop.

DRUG INTERACTIONS

Caution should be exercised when considering the coadministration of ANORO with ketoconazole and other known strong CYP3A4 inhibitors as increased systemic exposure to vilanterol and cardiovascular adverse effects may occur. See prior Warning and Precaution regarding CYP3A4 inhibitors.

ANORO should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval, or within 2 weeks of discontinuation of such agents, because they may potentiate the effect of vilanterol on the cardiovascular system.

Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as vilanterol, but may produce severe bronchospasm in patients with COPD.

Use with caution in patients taking non–potassium-sparing diuretics, as ECG changes and/or hypokalemia associated with these diuretics may worsen with concomitant beta-agonists.

Avoid coadministration of ANORO with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.

Important Safety Information for ADVAIR DISKUS 250/50 for COPD

CONTRAINDICATIONS

ADVAIR DISKUS is contraindicated for primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.

ADVAIR DISKUS is contraindicated in patients with severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients.

Important Safety Information for ADVAIR DISKUS 250/50 for COPD

CONTRAINDICATIONS

ADVAIR DISKUS is contraindicated for primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.

ADVAIR DISKUS is contraindicated in patients with severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients.

WARNINGS AND PRECAUTIONS

LABA monotherapy for asthma increases the risk of asthma-related death, and in pediatric and adolescent patients, available data also suggest an increased risk of asthma-related hospitalization. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.

ADVAIR DISKUS should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD.

ADVAIR DISKUS should not be used for the relief of acute symptoms, ie, as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not ADVAIR DISKUS, should be used to relieve acute symptoms such as shortness of breath.

ADVAIR DISKUS should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using ADVAIR DISKUS should not use another medicine containing a LABA (eg, salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol, vilanterol) for any reason.

Oropharyngeal candidiasis has occurred in patients treated with ADVAIR DISKUS. Advise patients to rinse the mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

There is an increased risk of pneumonia with ADVAIR DISKUS in patients with COPD.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical features of pneumonia and exacerbations frequently overlap.

– In 2 replicate 1-year trials in 1579 subjects with COPD with a history of exacerbations, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in subjects treated with ADVAIR DISKUS 250/50 was higher in subjects over 65 years of age (9%) compared to the incidence in subjects under 65 years of age (4%).

– In a 3-year trial in 6184 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 500/50 compared with placebo (16% receiving ADVAIR DISKUS 500/50, 14% receiving fluticasone propionate 500 mcg, 11% receiving salmeterol 50 mcg, and 9% receiving placebo). The incidence of pneumonia was higher in subjects over 65 years of age (18% with ADVAIR DISKUS 500/50 vs 10% with placebo) compared with subjects less than 65 years of age (14% with ADVAIR DISKUS 500/50 vs 8% with placebo).

Patients who use corticosteroids are at risk for potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. A more serious or even fatal course of chickenpox or measles may occur in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections.

Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. Slowly taper the dose of systemic corticosteroids if transferring patients to ADVAIR DISKUS.

Hypercorticism and adrenal suppression may occur with high doses of inhaled corticosteroids, including fluticasone propionate, or at the recommended dose in susceptible individuals. If such effects occur, discontinue ADVAIR DISKUS slowly.

Salmeterol, a component of ADVAIR DISKUS, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. If such effects occur, ADVAIR DISKUS may need to be discontinued. ADVAIR DISKUS should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (eg, anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating ADVAIR DISKUS 250/50 and periodically thereafter.

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long‐term administration of inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR DISKUS. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

Be alert to hypokalemia, hyperglycemia, and systemic eosinophilic conditions, such as Churg-Strauss syndrome.

Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

In the two 1-year trials, the most common events that occurred with a frequency of >5% and more frequently in the subjects treated with ADVAIR DISKUS 250/50 than with salmeterol were nasopharyngitis, upper respiratory tract infection, nasal congestion, back pain, sinusitis, dizziness, nausea, pneumonia, candidiasis, and dysphonia.

ADVAIR DISKUS should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of ADVAIR DISKUS, on the vascular system may be potentiated by these agents.

Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of ADVAIR DISKUS, but may also produce severe bronchospasm in patients with asthma or COPD.

Use ADVAIR DISKUS with caution in patients taking non–potassium-sparing diuretics (such as loop or thiazide diuretics), as electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with coadministration with beta-agonists, such as salmeterol.

USE IN SPECIFIC POPULATIONS

Fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism. Impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.

The effects of corticosteroids in the treatment of COPD are not well defined, and inhaled corticosteroids, when used apart from approved combination products, are not indicated for COPD.

Important Safety Information for INCRUSE ELLIPTA

CONTRAINDICATIONS

The use of INCRUSE ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have hypersensitivity to umeclidinium or any of the excipients.

WARNINGS AND PRECAUTIONS

INCRUSE ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD.

INCRUSE ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

Use with caution in patients with narrow-angle glaucoma. Instruct patients to contact a healthcare provider immediately if signs or symptoms of acute narrow-angle glaucoma develop.

Use with caution in patients with urinary retention, especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to contact a healthcare provider immediately if signs or symptoms of urinary retention develop.

In addition to the adverse reactions reported in the umeclidinium monotherapy trials, adverse reactions reported in four 12-week trials with INCRUSE ELLIPTA in combination with an inhaled corticosteroid/long-acting beta2-adrenergic agonist (ICS/LABA), at an incidence of ≥1% and exceeding ICS/LABA alone, were oropharyngeal pain and dysgeusia.

DRUG INTERACTIONS

Avoid coadministration of INCRUSE ELLIPTA with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.

Indication for ANORO ELLIPTA

ANORO is for the once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. ANORO is NOT for the relief of acute bronchospasm or for asthma.

Indications for ADVAIR DISKUS 250/50 for COPD

Twice-daily ADVAIR DISKUS 250/50 is for maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema, and for reducing COPD exacerbations in patients with a history of exacerbations. ADVAIR DISKUS 250/50 is the only strength indicated for COPD. ADVAIR DISKUS 250/50 is NOT indicated for the relief of acute bronchospasm.

Important Safety Information for ANORO ELLIPTA

WARNING: ASTHMA-RELATED DEATH

Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, one of the active ingredients in ANORO, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths. This finding with salmeterol is considered a class effect of all LABA.

The safety and efficacy of ANORO in patients with asthma have not been established. ANORO is not indicated for the treatment of asthma.

CONTRAINDICATIONS

ANORO is contraindicated in patients with severe hypersensitivity to milk proteins or with hypersensitivity to umeclidinium, vilanterol, or any of the excipients.

WARNINGS AND PRECAUTIONS

ANORO should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD.

ANORO is NOT a rescue medication and should NOT be used for the relief of acute bronchospasm or symptoms. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

ANORO should not be used more often or at higher doses than recommended or with another LABA (eg, salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs, like LABA.

Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of ANORO. Discontinue ANORO if such reactions occur.

Vilanterol can produce clinically significant cardiovascular effects in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, or symptoms. If such effects occur, ANORO may need to be discontinued. ANORO should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

Use with caution in patients with narrow-angle glaucoma. Instruct patients to contact a healthcare provider immediately if signs or symptoms of acute narrow-angle glaucoma develop.

Use with caution in patients with urinary retention, especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to contact a healthcare provider immediately if signs or symptoms of urinary retention develop.

DRUG INTERACTIONS

Caution should be exercised when considering the coadministration of ANORO with ketoconazole and other known strong CYP3A4 inhibitors as increased systemic exposure to vilanterol and cardiovascular adverse effects may occur. See prior Warning and Precaution regarding CYP3A4 inhibitors.

ANORO should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval, or within 2 weeks of discontinuation of such agents, because they may potentiate the effect of vilanterol on the cardiovascular system.

Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as vilanterol, but may produce severe bronchospasm in patients with COPD.

Use with caution in patients taking non–potassium-sparing diuretics, as ECG changes and/or hypokalemia associated with these diuretics may worsen with concomitant beta-agonists.

Avoid coadministration of ANORO with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.

Important Safety Information for ADVAIR DISKUS 250/50 for COPD

CONTRAINDICATIONS

ADVAIR DISKUS is contraindicated for primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.

ADVAIR DISKUS is contraindicated in patients with severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients.

Important Safety Information for ADVAIR DISKUS 250/50 for COPD

CONTRAINDICATIONS

ADVAIR DISKUS is contraindicated for primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.

ADVAIR DISKUS is contraindicated in patients with severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients.

WARNINGS AND PRECAUTIONS

LABA monotherapy for asthma increases the risk of asthma-related death, and in pediatric and adolescent patients, available data also suggest an increased risk of asthma-related hospitalization. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.

ADVAIR DISKUS should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD.

ADVAIR DISKUS should not be used for the relief of acute symptoms, ie, as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not ADVAIR DISKUS, should be used to relieve acute symptoms such as shortness of breath.

ADVAIR DISKUS should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using ADVAIR DISKUS should not use another medicine containing a LABA (eg, salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol, vilanterol) for any reason.

Oropharyngeal candidiasis has occurred in patients treated with ADVAIR DISKUS. Advise patients to rinse the mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

There is an increased risk of pneumonia with ADVAIR DISKUS in patients with COPD.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical features of pneumonia and exacerbations frequently overlap.

– In 2 replicate 1-year trials in 1579 subjects with COPD with a history of exacerbations, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in subjects treated with ADVAIR DISKUS 250/50 was higher in subjects over 65 years of age (9%) compared to the incidence in subjects under 65 years of age (4%).

– In a 3-year trial in 6184 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 500/50 compared with placebo (16% receiving ADVAIR DISKUS 500/50, 14% receiving fluticasone propionate 500 mcg, 11% receiving salmeterol 50 mcg, and 9% receiving placebo). The incidence of pneumonia was higher in subjects over 65 years of age (18% with ADVAIR DISKUS 500/50 vs 10% with placebo) compared with subjects less than 65 years of age (14% with ADVAIR DISKUS 500/50 vs 8% with placebo).

Patients who use corticosteroids are at risk for potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. A more serious or even fatal course of chickenpox or measles may occur in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections.

Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. Slowly taper the dose of systemic corticosteroids if transferring patients to ADVAIR DISKUS.

Hypercorticism and adrenal suppression may occur with high doses of inhaled corticosteroids, including fluticasone propionate, or at the recommended dose in susceptible individuals. If such effects occur, discontinue ADVAIR DISKUS slowly.

Salmeterol, a component of ADVAIR DISKUS, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. If such effects occur, ADVAIR DISKUS may need to be discontinued. ADVAIR DISKUS should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (eg, anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating ADVAIR DISKUS 250/50 and periodically thereafter.

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long‐term administration of inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR DISKUS. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

Be alert to hypokalemia, hyperglycemia, and systemic eosinophilic conditions, such as Churg-Strauss syndrome.

Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

In the two 1-year trials, the most common events that occurred with a frequency of >5% and more frequently in the subjects treated with ADVAIR DISKUS 250/50 than with salmeterol were nasopharyngitis, upper respiratory tract infection, nasal congestion, back pain, sinusitis, dizziness, nausea, pneumonia, candidiasis, and dysphonia.

ADVAIR DISKUS should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of ADVAIR DISKUS, on the vascular system may be potentiated by these agents.

Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of ADVAIR DISKUS, but may also produce severe bronchospasm in patients with asthma or COPD.

Use ADVAIR DISKUS with caution in patients taking non–potassium-sparing diuretics (such as loop or thiazide diuretics), as electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with coadministration with beta-agonists, such as salmeterol.

USE IN SPECIFIC POPULATIONS

Fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism. Impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.

The effects of corticosteroids in the treatment of COPD are not well defined, and inhaled corticosteroids, when used apart from approved combination products, are not indicated for COPD.

Important Safety Information for ANORO ELLIPTA

WARNING: ASTHMA-RELATED DEATH

Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, one of the active ingredients in ANORO, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths. This finding with salmeterol is considered a class effect of all LABA.

The safety and efficacy of ANORO in patients with asthma have not been established. ANORO is not indicated for the treatment of asthma.

CONTRAINDICATIONS

ANORO is contraindicated in patients with severe hypersensitivity to milk proteins or with hypersensitivity to umeclidinium, vilanterol, or any of the excipients.

WARNINGS AND PRECAUTIONS

ANORO should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD.

ANORO is NOT a rescue medication and should NOT be used for the relief of acute bronchospasm or symptoms. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

ANORO should not be used more often or at higher doses than recommended or with another LABA (eg, salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs, like LABA.

Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of ANORO. Discontinue ANORO if such reactions occur.

Vilanterol can produce clinically significant cardiovascular effects in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, or symptoms. If such effects occur, ANORO may need to be discontinued. ANORO should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

Use with caution in patients with narrow-angle glaucoma. Instruct patients to contact a healthcare provider immediately if signs or symptoms of acute narrow-angle glaucoma develop.

Use with caution in patients with urinary retention, especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to contact a healthcare provider immediately if signs or symptoms of urinary retention develop.

DRUG INTERACTIONS

Caution should be exercised when considering the coadministration of ANORO with ketoconazole and other known strong CYP3A4 inhibitors as increased systemic exposure to vilanterol and cardiovascular adverse effects may occur. See prior Warning and Precaution regarding CYP3A4 inhibitors.

ANORO should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval, or within 2 weeks of discontinuation of such agents, because they may potentiate the effect of vilanterol on the cardiovascular system.

Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as vilanterol, but may produce severe bronchospasm in patients with COPD.

Use with caution in patients taking non–potassium-sparing diuretics, as ECG changes and/or hypokalemia associated with these diuretics may worsen with concomitant beta-agonists.

Avoid coadministration of ANORO with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.

Important Safety Information for ADVAIR DISKUS 250/50 for COPD

CONTRAINDICATIONS

ADVAIR DISKUS is contraindicated for primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.

ADVAIR DISKUS is contraindicated in patients with severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients.

Important Safety Information for ADVAIR DISKUS 250/50 for COPD

CONTRAINDICATIONS

ADVAIR DISKUS is contraindicated for primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.

ADVAIR DISKUS is contraindicated in patients with severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients.

WARNINGS AND PRECAUTIONS

LABA monotherapy for asthma increases the risk of asthma-related death, and in pediatric and adolescent patients, available data also suggest an increased risk of asthma-related hospitalization. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.

ADVAIR DISKUS should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD.

ADVAIR DISKUS should not be used for the relief of acute symptoms, ie, as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not ADVAIR DISKUS, should be used to relieve acute symptoms such as shortness of breath.

ADVAIR DISKUS should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using ADVAIR DISKUS should not use another medicine containing a LABA (eg, salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol, vilanterol) for any reason.

Oropharyngeal candidiasis has occurred in patients treated with ADVAIR DISKUS. Advise patients to rinse the mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

There is an increased risk of pneumonia with ADVAIR DISKUS in patients with COPD.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical features of pneumonia and exacerbations frequently overlap.

– In 2 replicate 1-year trials in 1579 subjects with COPD with a history of exacerbations, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in subjects treated with ADVAIR DISKUS 250/50 was higher in subjects over 65 years of age (9%) compared to the incidence in subjects under 65 years of age (4%).

– In a 3-year trial in 6184 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 500/50 compared with placebo (16% receiving ADVAIR DISKUS 500/50, 14% receiving fluticasone propionate 500 mcg, 11% receiving salmeterol 50 mcg, and 9% receiving placebo). The incidence of pneumonia was higher in subjects over 65 years of age (18% with ADVAIR DISKUS 500/50 vs 10% with placebo) compared with subjects less than 65 years of age (14% with ADVAIR DISKUS 500/50 vs 8% with placebo).

Patients who use corticosteroids are at risk for potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. A more serious or even fatal course of chickenpox or measles may occur in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections.

Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. Slowly taper the dose of systemic corticosteroids if transferring patients to ADVAIR DISKUS.

Hypercorticism and adrenal suppression may occur with high doses of inhaled corticosteroids, including fluticasone propionate, or at the recommended dose in susceptible individuals. If such effects occur, discontinue ADVAIR DISKUS slowly.

Salmeterol, a component of ADVAIR DISKUS, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. If such effects occur, ADVAIR DISKUS may need to be discontinued. ADVAIR DISKUS should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (eg, anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating ADVAIR DISKUS 250/50 and periodically thereafter.

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long‐term administration of inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR DISKUS. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

Be alert to hypokalemia, hyperglycemia, and systemic eosinophilic conditions, such as Churg-Strauss syndrome.

Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

In the two 1-year trials, the most common events that occurred with a frequency of >5% and more frequently in the subjects treated with ADVAIR DISKUS 250/50 than with salmeterol were nasopharyngitis, upper respiratory tract infection, nasal congestion, back pain, sinusitis, dizziness, nausea, pneumonia, candidiasis, and dysphonia.

ADVAIR DISKUS should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of ADVAIR DISKUS, on the vascular system may be potentiated by these agents.

Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of ADVAIR DISKUS, but may also produce severe bronchospasm in patients with asthma or COPD.

Use ADVAIR DISKUS with caution in patients taking non–potassium-sparing diuretics (such as loop or thiazide diuretics), as electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with coadministration with beta-agonists, such as salmeterol.

USE IN SPECIFIC POPULATIONS

Fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism. Impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.

The effects of corticosteroids in the treatment of COPD are not well defined, and inhaled corticosteroids, when used apart from approved combination products, are not indicated for COPD.

Important Safety Information for ANORO ELLIPTA

WARNING: ASTHMA-RELATED DEATH

Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, one of the active ingredients in ANORO, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths. This finding with salmeterol is considered a class effect of all LABA.

The safety and efficacy of ANORO in patients with asthma have not been established. ANORO is not indicated for the treatment of asthma.

CONTRAINDICATIONS

ANORO is contraindicated in patients with severe hypersensitivity to milk proteins or with hypersensitivity to umeclidinium, vilanterol, or any of the excipients.

WARNINGS AND PRECAUTIONS

ANORO should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD.

ANORO is NOT a rescue medication and should NOT be used for the relief of acute bronchospasm or symptoms. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

ANORO should not be used more often or at higher doses than recommended or with another LABA (eg, salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs, like LABA.

Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of ANORO. Discontinue ANORO if such reactions occur.

Vilanterol can produce clinically significant cardiovascular effects in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, or symptoms. If such effects occur, ANORO may need to be discontinued. ANORO should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

Use with caution in patients with narrow-angle glaucoma. Instruct patients to contact a healthcare provider immediately if signs or symptoms of acute narrow-angle glaucoma develop.

Use with caution in patients with urinary retention, especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to contact a healthcare provider immediately if signs or symptoms of urinary retention develop.

DRUG INTERACTIONS

Caution should be exercised when considering the coadministration of ANORO with ketoconazole and other known strong CYP3A4 inhibitors as increased systemic exposure to vilanterol and cardiovascular adverse effects may occur. See prior Warning and Precaution regarding CYP3A4 inhibitors.

ANORO should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval, or within 2 weeks of discontinuation of such agents, because they may potentiate the effect of vilanterol on the cardiovascular system.

Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as vilanterol, but may produce severe bronchospasm in patients with COPD.

Use with caution in patients taking non–potassium-sparing diuretics, as ECG changes and/or hypokalemia associated with these diuretics may worsen with concomitant beta-agonists.

Avoid coadministration of ANORO with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.

Important Safety Information for ADVAIR DISKUS 250/50 for COPD

CONTRAINDICATIONS

ADVAIR DISKUS is contraindicated for primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.

ADVAIR DISKUS is contraindicated in patients with severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients.

Important Safety Information for ADVAIR DISKUS 250/50 for COPD

CONTRAINDICATIONS

ADVAIR DISKUS is contraindicated for primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.

ADVAIR DISKUS is contraindicated in patients with severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients.

WARNINGS AND PRECAUTIONS

LABA monotherapy for asthma increases the risk of asthma-related death, and in pediatric and adolescent patients, available data also suggest an increased risk of asthma-related hospitalization. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.

ADVAIR DISKUS should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD.

ADVAIR DISKUS should not be used for the relief of acute symptoms, ie, as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not ADVAIR DISKUS, should be used to relieve acute symptoms such as shortness of breath.

ADVAIR DISKUS should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using ADVAIR DISKUS should not use another medicine containing a LABA (eg, salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol, vilanterol) for any reason.

Oropharyngeal candidiasis has occurred in patients treated with ADVAIR DISKUS. Advise patients to rinse the mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

There is an increased risk of pneumonia with ADVAIR DISKUS in patients with COPD.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical features of pneumonia and exacerbations frequently overlap.

– In 2 replicate 1-year trials in 1579 subjects with COPD with a history of exacerbations, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 250/50 (7%) than in those receiving salmeterol 50 mcg (3%). The incidence of pneumonia in subjects treated with ADVAIR DISKUS 250/50 was higher in subjects over 65 years of age (9%) compared to the incidence in subjects under 65 years of age (4%).

– In a 3-year trial in 6184 subjects with COPD, there was a higher incidence of pneumonia reported in subjects receiving ADVAIR DISKUS 500/50 compared with placebo (16% receiving ADVAIR DISKUS 500/50, 14% receiving fluticasone propionate 500 mcg, 11% receiving salmeterol 50 mcg, and 9% receiving placebo). The incidence of pneumonia was higher in subjects over 65 years of age (18% with ADVAIR DISKUS 500/50 vs 10% with placebo) compared with subjects less than 65 years of age (14% with ADVAIR DISKUS 500/50 vs 8% with placebo).

Patients who use corticosteroids are at risk for potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. A more serious or even fatal course of chickenpox or measles may occur in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections.

Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. Slowly taper the dose of systemic corticosteroids if transferring patients to ADVAIR DISKUS.

Hypercorticism and adrenal suppression may occur with high doses of inhaled corticosteroids, including fluticasone propionate, or at the recommended dose in susceptible individuals. If such effects occur, discontinue ADVAIR DISKUS slowly.

Salmeterol, a component of ADVAIR DISKUS, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. If such effects occur, ADVAIR DISKUS may need to be discontinued. ADVAIR DISKUS should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (eg, anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating ADVAIR DISKUS 250/50 and periodically thereafter.

Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long‐term administration of inhaled corticosteroids, including fluticasone propionate, a component of ADVAIR DISKUS. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

Be alert to hypokalemia, hyperglycemia, and systemic eosinophilic conditions, such as Churg-Strauss syndrome.

Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

In the two 1-year trials, the most common events that occurred with a frequency of >5% and more frequently in the subjects treated with ADVAIR DISKUS 250/50 than with salmeterol were nasopharyngitis, upper respiratory tract infection, nasal congestion, back pain, sinusitis, dizziness, nausea, pneumonia, candidiasis, and dysphonia.

ADVAIR DISKUS should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of ADVAIR DISKUS, on the vascular system may be potentiated by these agents.

Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of ADVAIR DISKUS, but may also produce severe bronchospasm in patients with asthma or COPD.

Use ADVAIR DISKUS with caution in patients taking non–potassium-sparing diuretics (such as loop or thiazide diuretics), as electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with coadministration with beta-agonists, such as salmeterol.

USE IN SPECIFIC POPULATIONS

Fluticasone propionate and salmeterol are predominantly cleared by hepatic metabolism. Impairment of liver function may lead to accumulation of fluticasone propionate and salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.

The effects of corticosteroids in the treatment of COPD are not well defined, and inhaled corticosteroids, when used apart from approved combination products, are not indicated for COPD.

Important Safety Information for INCRUSE ELLIPTA

CONTRAINDICATIONS

The use of INCRUSE ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have hypersensitivity to umeclidinium or any of the excipients.

WARNINGS AND PRECAUTIONS

INCRUSE ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD.

INCRUSE ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

Use with caution in patients with narrow-angle glaucoma. Instruct patients to contact a healthcare provider immediately if signs or symptoms of acute narrow-angle glaucoma develop.

Use with caution in patients with urinary retention, especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to contact a healthcare provider immediately if signs or symptoms of urinary retention develop.

In addition to the adverse reactions reported in the umeclidinium monotherapy trials, adverse reactions reported in four 12-week trials with INCRUSE ELLIPTA in combination with an inhaled corticosteroid/long-acting beta2-adrenergic agonist (ICS/LABA), at an incidence of ≥1% and exceeding ICS/LABA alone, were oropharyngeal pain and dysgeusia.

DRUG INTERACTIONS

Avoid coadministration of INCRUSE ELLIPTA with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.

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